Gradalis Announces Publication in Nature Communications Medicine Identifying Survival Predicting Biomarker in Patients with Ovarian Cancer Treated with Vigil®

• Analysis identified high expression of ENTPD1 gene in patients at baseline as a significant predictor of overall and recurrence-free survival following Vigil treatment, relative to placebo

• This finding may allow for enhanced targeting of patients who will benefit from Vigil therapy

• Planned Phase 3 registrational trial for Vigil will aim to confirm ENTPD1 gene’s predictive value of treatment effect

DALLAS, Aug. 29, 2022 (GLOBE NEWSWIRE) — Gradalis Inc. announced a peer-reviewed publication today in the Nature portfolio journal, Communications Medicine, in which several biomarkers were evaluated for their potential to predict survival following Vigil^® (Gemogenovatucel-T) treatment. The publication entitled “ENTPD1 as a Predictive Marker of Treatment Response to Gemogenovatucel-T as Maintenance Therapy in Newly Diagnosed Ovarian Cancer,” features results from VITAL, a Phase 2b randomized, double-blind, placebo-controlled trial of Vigil in patients with newly diagnosed ovarian cancer. The analysis indicates that pretreatment expression levels of the ENTPD1 gene may be a significant predictor of overall survival (OS) and recurrence-free survival (RFS) following Vigil therapy. Vigil is a novel, personalized cellular immunotherapy platform that is designed to decloak the full repertoire of a patient’s tumor antigens, reactivate the immune system, and summon key effector cells to deliver a durable clinical response. In VITAL, Vigil showed a positive trend in RFS in the overall population and a significant improvement in RFS and OS in newly diagnosed ovarian cancer patients with BRCAwt and HRP molecular profiles. This finding may allow for a more refined targeting of patients who will benefit from Vigil therapy.

The ENTPD1 gene, also referred to as CD39, is a protein coding gene that functions as a limiting step in the adenosine metabolic pathway found in immunosuppressive tumor microenvironments. ENTPD1 gene directed signaling is involved in a wide range of cancers.
In the analysis, a high level of RNA expression by the ENTPD1 gene (High ENTPD1) was prospectively defined as greater than the median value, hence representing 50% of patients. High ENTPD1 was associated with improved RFS and OS following Vigil maintenance treatment in frontline ovarian cancer patients. The analysis was conducted in collaboration with the University of South Alabama.

“While the use of predictive biomarkers to identify populations most likely to benefit from immunotherapy has expanded and evolved, attempts to use this approach in the treatment of ovarian cancer have thus far been underwhelming,” said Rodney Rocconi, M.D., Professor, Obstetrics and Gynecology at University of Alabama at Birmingham and study investigator. “The Phase 2b VITAL trial demonstrated statistically significant improvement in RFS and OS when Vigil was used as a frontline maintenance therapy in patients with BRCAwt as well as HRP subtype advanced ovarian cancer. These exciting data and the identification of ENTPD1 as a biomarker that is predictive of response to Vigil, independent of BRCAwt and HRP status, represent a promising step forward with the potential to provide meaningful benefits for ovarian cancer patients.”

The full text of the article can be found here: https://www.nature.com/articles/s43856-022-00163-y. Key findings in the paper include:

• High ENTPD1 expression predicts response to Vigil versus placebo regardless of HR status: At 40 months elapsed, median RFS was not yet reached in the Vigil treated group (n=23) vs. 8.1 months in the placebo group (n=23), p=0.00007; at 40 months elapsed, median OS was not yet reached in the Vigil treated group vs. 41.4 months in the placebo group, p=0.013.
• High ENTPD1 expression with HRP status: RFS and OS were further improved in Vigil patients with tumors demonstrating High ENTPD1 and HRP status compared to the placebo group. Median RFS of 21.1 months was observed in the Vigil treated group (n=11) vs. 5.6 months in the placebo group (n=9), HR=0.18, p=0.004; at 40 months elapsed, median OS was not yet reached in the Vigil treated group vs. 27 months in the placebo group, HR=0.23, p=0.025.

John Nemunaitis, M.D., Chief Scientific Officer of Gradalis commented, “ENTPD1 is recognized to be an important gene in cancer development and progression. ENTPD1 has been identified as playing a role in numerous other solid tumor indications, including melanoma, lung cancer and colorectal cancer. There has been growing interest and support from large pharmaceutical companies for the development of drugs targeting the ENTPD1/CD39 axis. The findings published today further underscore the clinical utility of biomarker approaches to predict survival differences across BRCAwt and HRP positive ovarian cancer patients treated with Vigil. We plan to further validate these findings in the Vigil registrational program and hope to use such a biomarker-based patient selection strategy to expand the potential of Vigil across a variety of cancers.”

Mr. Steven Engle, Chief Executive Officer of Gradalis added, “In 2003, Gradalis’ founders including our CSO, Dr. Nemunaitis, had the foresight to explore more effective solutions to treat cancer, including approaches that leveraged the patient’s immune system to target the entire tumor. Based on multiple clinical studies, Gradalis has developed Vigil, an oncology treatment that is designed to decloak the full repertoire of a patient’s tumor antigens, reactivate the immune system, and summon key effector cells to deliver a durable clinical response. When combined, this powerful trifecta of anti-cancer activity has the potential to eliminate elusive metastatic cells and thus improve survival, as shown in our Phase 2 clinical studies in ovarian cancer.”

Mr. Engle continued, “Importantly, Vigil activates the patient’s immune system without disrupting its natural state of balance. As a result, multiple clinical trials have demonstrated that Vigil is well tolerated and has an encouraging safety profile compared to currently approved standard of care treatment options. Taken together, we believe Vigil has the potential to become a game-changing therapeutic approach in oncology. If validated in a planned Phase 3 trial, the ENTPD1 finding may be applicable to multiple cancer tumor types, providing the potential to explore new opportunities to maximize the therapeutic benefit of Vigil.”

About Ovarian Cancer and Molecular Profiles
Every year, an estimated 22,000 patients are diagnosed with ovarian cancer in the U.S. and 14,000 patients die. The biomarker analysis in the VITAL Phase 2b trial focused on patients with ovarian cancer who had the BRCA wildtype (BRCAwt) gene and whose tumors had the homologous recombination proficient (HRP) molecular profile. Patients with the BRCAwt molecular profile have less than a 35% chance of surviving ovarian cancer at five years following diagnosis. BRCAwt is found in over 75% of patients with ovarian cancer and in 90% or more of several other tumor types. Patients with the HRP molecular profile have less than a 30% chance of surviving ovarian cancer at five years following diagnosis. HRP is found in over 40% of patients with ovarian cancer and in 80% or more of several other tumor types, including skin, colorectal and cervical cancers.

BRCA genes produce proteins that help repair damaged DNA and are sometimes called tumor suppressor genes. There are two types of BRCA genes: BRCA wildtype (BRCAwt) and BRCA mutated (BRCAmt) gene. In tumors of patients with the BRCAwt gene, mutations that lead to the generation of novel neoantigens on the cell membrane of each cell are less likely to occur. As a result, it is easier for the immune system to identify and target the tumor cells. In patients with the BRCAmt gene, mutations are more likely to lead to the generation of different neoantigens on the cell membrane of each new tumor cell making it more difficult for the immune system to identify and target the tumor cells. Vigil uses the patient’s immune system to target the tumor, so it is not surprising that Vigil would work better in patients with the BRCAwt gene. Similarly, tumors with the HRP molecular profile are more likely to maintain intact DNA repair pathways, and therefore are also more likely to respond to Vigil therapy.

About Vigil
Vigil® is a novel, plasmid engineered, autologous tumor cell immunotherapy platform designed to achieve a trifecta of immune anticancer activity using a unique bi-shRNA DNA based technology and the patient’s own tumor tissue. The trifecta of systemic activity involves knock down of TGFβ1 and TGFβ2 which function as tumor suppressor cytokines, increased GM-CSF expression to enhance local immune function and presentation of the patient’s clonal neoantigen epitopes via use of autologous cancer tissue. By utilizing the patient’s own tumor as the antigen source, Vigil is designed to elicit an immune response that is specifically targeted and broadly relevant to each patient’s unique “clonal” tumor neoantigens. Vigil therapy has been well tolerated in Phase 1, 2a and 2b clinical studies.

In VITAL, a multicenter, randomized, double-blind, placebo-controlled Phase 2b trial (NCT02346747), Vigil showed a positive trend in the primary endpoint of recurrence free survival (RFS) in the overall population and a statistically significant improvement in RFS and overall survival (OS), with a median time of three years to date, in a pre-planned subgroup analysis of Stage III/IV newly diagnosed ovarian cancer patients with the BRCAwt molecular profile. In patients with tumors of the HRP type, significant additional improvement was seen in RFS and OS.

Additionally, Phase 1 results in an “all-comer” clinical trial have shown positive signals of activity in 19 tumor types and some patients treated with Vigil remain in the trial 48 months later. The company is preparing to initiate a clinical trial intended for product registration in patients with the HRP subtype ovarian cancer.

About Gradalis, Inc.
Founded in 2003, Gradalis is a privately held, late-stage clinical biotechnology company developing a personalized immunotherapy called Vigil, that has been tested in multiple studies in ovarian and other cancer tumor types. Based on its Phase 2b clinical trial results, the company is preparing to initiate a Phase 3 trial intended for product registration of Vigil in patients with ovarian cancer. Vigil is the first cellular immunotherapy to demonstrate survival benefits in a randomized controlled trial of patients with solid tumors. The results of the company’s Phase 2b trial have been published in Lancet Oncology and presented at the American Society of Clinical Oncology. Vigil is being studied in other women’s cancer types and has shown positive results in combination with checkpoint inhibitors

Gradalis’ Vigil platform uses the patient’s immune system to target the entire tumor. Based on multiple clinical studies, Gradalis has developed an oncology platform that is designed to decloak the full repertoire of a patient’s tumor antigens, reactivate the immune system, and summon key effector cells to deliver a durable clinical response. When combined, these are a powerful Trifecta of anti-cancer activities, potentially eliminating even the elusive metastatic cells, and as shown in Phase 2 clinical studies in ovarian cancer, a potential gamechanger in oncology. Our clinical trials have also demonstrated that Gradalis’ platform is better tolerated compared to standard cancer treatments since Vigil uses the patient’s immune system operating within its natural state of balance rather than in an artificial overdrive as with some technologies. Vigil utilizes proprietary bi-shRNA technology that has been proven to silence multiple genes in a variety of cancers and has the potential to be used in other diseases.

Forward-Looking Statements
This press release contains forward-looking statements, including, without limitation, statements regarding the success, cost, and timing of our product development activities and clinical trials, our plans to research, develop, and commercialize our product candidates, and our plans to submit regulatory filings and obtain regulatory approval of our product candidates. These forward-looking statements are based on Gradalis’ current expectations and assumptions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks, and changes in circumstances that may differ materially from those contemplated by the forward-looking statements, which are neither statements of historical fact nor guarantees or assurances of future performance. Important factors that could cause actual results to differ materially from those in the forward-looking statements include but are not limited to: (a) the timing, costs, and outcomes of our clinical trials and preclinical studies, (b) the timing and likelihood of regulatory filings and approvals for our product candidates, and (c) the potential market size for our product candidates. These forward-looking statements speak only as of the date made and, other than as required by law, we undertake no obligation to publicly update or revise any forward-looking statements. This press release does not constitute an offer to sell, or a solicitation of an offer to buy, any securities.

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